Tuberous sclerosis complex: molecular pathogenesis, multidisciplinary management and future therapy

Background Tuberous sclerosis complex (TSC) is a rare, autosomal dominant neurocutaneous disorder caused by pathogenic variants in TSC1 or TSC2 , leading to constitutive hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. This dysregulation drives the formation of benign hamartomas across multiple organ systems, including the brain, skin, kidneys, heart, and lungs. TSC exhibits complete penetrance but remarkably variable expressivity, posing significant diagnostic and management challenges. Main body This comprehensive review synthesizes the pathogenesis, clinical manifestations, and therapeutic advancements in TSC. We detail the updated 2021 diagnostic criteria, which prioritize specific neuroimaging and clinical features. The spectrum of neurologic morbidity is explored, focusing on epilepsy affecting up to 90% of patients and TSC-Associated Neuropsychiatric Disorders (TAND), a nearly universal comorbidity encompassing intellectual disability, autism spectrum disorder, and behavioral challenges. We examine the age-dependent evolution of major manifestations, including subependymal giant cell astrocytomas (SEGAs), renal angiomyolipomas (AMLs), and lymphangioleiomyomatosis (LAM). The review highlights the paradigm shift driven by mTOR inhibitors (everolimus, sirolimus), whose efficacy in landmark EXIST trials has transformed care for SEGAs, AML, and LAM. We discuss the preventive use of vigabatrin for epilepsy, as evidenced by the EPISTOP trial, and the critical role of lifelong, multidisciplinary surveillance. We also critically appraise limitations of current evidence, including variable efficacy of mTOR inhibition across organ systems, unmet needs in TAND management, and challenges of lifelong therapy. Emerging frontiers, synthetic lethality strategies, genetic medicine (gene augmentation, CRISPR-Cas9, base/prime editing), and AI-driven precision care—are synthesized within a unified therapeutic trajectory. Conclusion The management of TSC has evolved from reactive intervention to proactive, mechanism-driven precision medicine. Despite transformative advances, significant challenges remain, including TAND management, disease heterogeneity, and global care equity. Future horizons are poised to move beyond chronic suppression toward curative strategies, including combinatorial therapies to induce synthetic lethality and pioneering genetic medicine approaches. This review underscores the imperative of integrated, multidisciplinary care to optimize outcomes and quality of life for individuals with TSC throughout their lifespan.